The CELF family of RNA binding proteins is implicated in cell-specific and developmentally regulated alternative splicing

Mol Cell Biol. 2001 Feb;21(4):1285-96. doi: 10.1128/MCB.21.4.1285-1296.2001.


Alternative splicing of cardiac troponin T (cTNT) exon 5 undergoes a developmentally regulated switch such that exon inclusion predominates in embryonic, but not adult, striated muscle. We previously described four muscle-specific splicing enhancers (MSEs) within introns flanking exon 5 in chicken cTNT that are both necessary and sufficient for exon inclusion in embryonic muscle. We also demonstrated that CUG-binding protein (CUG-BP) binds a conserved CUG motif within a human cTNT MSE and positively regulates MSE-dependent exon inclusion. Here we report that CUG-BP is one of a novel family of developmentally regulated RNA binding proteins that includes embryonically lethal abnormal vision-type RNA binding protein 3 (ETR-3). This family, which we call CELF proteins for CUG-BP- and ETR-3-like factors, specifically bound MSE-containing RNAs in vitro and activated MSE-dependent exon inclusion of cTNT minigenes in vivo. The expression of two CELF proteins is highly restricted to brain. CUG-BP, ETR-3, and CELF4 are more broadly expressed, and expression is developmentally regulated in striated muscle and brain. Changes in the level of expression and isoforms of ETR-3 in two different developmental systems correlated with regulated changes in cTNT splicing. A switch from cTNT exon skipping to inclusion tightly correlated with induction of ETR-3 protein expression during differentiation of C2C12 myoblasts. During heart development, the switch in cTNT splicing correlated with a transition in ETR-3 protein isoforms. We propose that ETR-3 is a major regulator of cTNT alternative splicing and that the CELF family plays an important regulatory role in cell-specific alternative splicing during normal development and disease.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Adult
  • Alternative Splicing*
  • Amino Acid Sequence
  • Animals
  • Base Sequence
  • Brain / growth & development
  • Brain / metabolism
  • CELF Proteins
  • CELF1 Protein
  • Cell Line
  • Chickens
  • DNA Primers / genetics
  • Enhancer Elements, Genetic
  • Exons
  • Female
  • Gene Expression
  • Humans
  • Male
  • Molecular Sequence Data
  • Muscle Development
  • Muscle, Skeletal / growth & development
  • Muscle, Skeletal / metabolism
  • Nerve Tissue Proteins
  • RNA-Binding Proteins / genetics*
  • RNA-Binding Proteins / metabolism*
  • Ribonucleoproteins / genetics
  • Sequence Homology, Amino Acid
  • Tissue Distribution
  • Troponin T / genetics


  • CELF Proteins
  • CELF1 Protein
  • CELF1 protein, human
  • CELF2 protein, human
  • CELF3 protein, human
  • CELF4 protein, human
  • CELF5 protein, human
  • DNA Primers
  • Nerve Tissue Proteins
  • RNA-Binding Proteins
  • Ribonucleoproteins
  • Troponin T

Associated data

  • GENBANK/AF329264
  • GENBANK/AF329265
  • GENBANK/AF329266